HER2-Targeted Gene Transfer

Abstract

Selective transfer of genes to specific cells remains a barrier to successful utilization of somatic gene therapy. We hypothesized that the human epidermal growth factor receptor-2 (HER2, also called ErbB2), a membrane tyrosine kinase highly expressed in many epithelial tumors, could be an immunological target for gene transfer. To test this hypothesis in vitro, we non-covalently linked a luciferase expression vector (pRSVLuc) to a humanized HER2 antibody (rhuMAbHER2) covalently modified with poly-l-lysine bridges (PL). This complex (PL–rhuMAbHER2) was tested for its ability to direct gene transfer to HER2 expressing cells in vitro using NIH3T3 (HER2 nonexpressing) and NIH3T3.HER2 (HER2 expressing) cell lines as a model system. Twenty-four hours after exposing NIH3T3.HER2 cells to the PL–rhuMAbHER2–pRSVLuc complexes and 100 μM chloroquine, luciferase expression was 180-fold higher than that obtained from a conjugate made with an isotype-matched antibody against an irrelevant target. Exposing the HER2-expressing adenocarcinoma cell lines BT474 and SKBR3 to the HER2-targeted complexes also resulted in successful gene transfer and expression. Gene transfer was specific for the HER2 receptor, because preincubation of HER2-expressing cells with unconjugated rhuMAbHER2 decreased complex-mediated luciferase expression by 95%. These studies suggest that HER2 may be an appropriate target for selective gene transfer and that PL–rhuMAbHER2–DNA complexes may be a useful vehicle for directing gene transfer to cells that express HER2.

Overview summary

Gene transfer as a treatment of cancer is dependent on the selective transfer of genes to specific cells. As a beginning step in such targeted therapy, we have developed a new gene transfer vehicle against a previously unused target, the HER2 receptor. The target has a restricted expression pattern and is highly over-expressed in many human tumors. The HER2-targeted gene transfer vehicle is specific for HER2-expressing cells. This target and vehicle holds potential as a new means of selective gene transfer to HER2-expressing cancers.